Method for producing octahydro-2(1H)-naphthalenone derivatives

Abstract

The present invention relates to the field of organic synthesis, more specifically to a method for preparing a compound of formula (I). Compounds of formula (V), compounds of formula (VI) and compounds of formula (VIII) are also part of the present invention.

Description

[Technical field]

[0001] The present invention relates to the field of organic synthesis, more specifically to a method for preparing a compound of formula (I). Compounds of formula (V), compounds of formula (VI) and compounds of formula (VIII) are also part of the present invention.

[0002] 2. Background of the Invention Octahydro-2(1H)-naphthalenone derivatives represent a highly desirable scaffold that can be used as such or as key intermediates useful for the preparation of more complex compounds in various fields, such as fragrance, cosmetics, pharmaceuticals or agrochemicals, among others. Octahydro-2(1H)-naphthalenone derivatives important in the fragrance industry include, for example, 5,5,8a-trimethyloctahydro-2(1H)-naphthalenone, which is a valuable intermediate to 5,5,8a-trimethyldecahydronaphthalen-2-yl acetate, one of the most sought-after components in the fragrance industry. Both compounds have several chiral centers and can take different stereoisomeric forms, but interest in fragrance is directed especially to the stereoisomer with trans-decalin. Starting from commercially available geraniol, the preparation of the compound of formula (I) with high selectivity for trans-decalin is reported in EP 579991 and requires eight chemical steps. WO 2020 / 173977 also discloses the production of the compound of formula (I) with high selectivity by cyclization of 6,10-dimethylundeca-1,5,9-triene or 6,10-dimethylundeca-5,9-dien-1-yne in the presence of squalenehopene cyclase. However, the conversion and yield are low, and the reaction time is very long, making the production of both starting materials industrially unfeasible.

[0003] Being an industrially important product, new methods are constantly being sought that show improved yield or productivity while limiting the number of steps without compromising selectivity. Recently, biotechnological methods for the production of ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol or ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate with high selectivity using host cells / microorganisms expressing the relevant enzymes have been reported in WO 2018 / 220113, WO 2019 / 229064 or WO 2020 / 078871. However, the conversion of those compounds to the compound of formula (I) has not been reported.

[0004] The present invention is a process for the preparation of compounds of formula (I) with high selectivity for the trans-decalin isomer starting from compounds of formula (II) and in a new route via new intermediates. In particular, the compounds of formulae (V), (VI) and (VIII) which are the subject of the present invention have never been reported in the prior art or suggested in the context of the preparation of compounds of formula (I). To the best of the inventors' knowledge, the process of the present invention or the compounds of formulae (V), (VI) and (VIII) of the present invention have never been reported in the prior art.

[0005] Summary of the Invention The present invention relates to a new process for preparing compounds of formula (I) starting from compounds of formula (II) and opening up a new route to compounds of formula (IV).

[0006] A first subject of the invention is therefore a compound of formula [ka] [In the formula, the bold and hatched lines indicate relative or absolute configurations] A method for preparing a compound of the formula: a) Formula [ka] [Wherein, X is vinyl, CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 is C 1-6 represents an alkyl group, R 2 is a hydrogen atom, a benzyl group, C(=O)R a Group, C(=O)OR b group, C(R c ) 2 OR d group or Si(R d ) 3 represents a group, R a is a hydrogen atom or C 1-6 is an alkyl group, R b is C 1-6 is an alkyl group, R c are each independently a hydrogen atom or C 1-2 is an alkyl group, R d is C 1-4 Either R is an alkyl group or c and R d Together, C 4-5 to form an oxacycloalkyl group, in the form of any one stereoisomer or mixtures thereof of the compound of the formula [ka] [In the formula, X' is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 and R 2 has the same meaning as defined above] in the form of any one stereoisomer or a mixture thereof; b) converting the intermediate of formula (III) into a compound of formula (I); The method includes:

[0007] A second subject of the invention is a compound of formula [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0008] A third subject of the invention is a compound of formula [ka] [In the formula, the bold and hatched lines indicate the relative or absolute configuration, and X is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 is C 1-6 represents an alkyl group, R 2 is a hydrogen atom, a benzyl group, C(=O)R a Group, C(=O)OR b group, C(R c ) 2 OR d group or Si(R d ) 3 represents a group, R a is a hydrogen atom or C 1-6 is an alkyl group, R b is C 1-6 is an alkyl group, R c are each independently a hydrogen atom or C 1-2 is an alkyl group, R d is C 1-4 Either R is an alkyl group or c and R d Together, C 4-5 The compound may be in the form of any one of the stereoisomers or a mixture thereof, wherein the compound forms an oxacycloalkyl group.

[0009] A further subject of the present invention is a compound of formula [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0010] Description of the Invention It has now surprisingly been found that compounds of formula (I) having a trans configuration can be obtained from compounds of formula (II), thereby reducing the number of steps while maintaining high selectivity and yield. The process of the present invention opens up a new route starting from natural products or derivatives of natural products, making it possible to obtain compounds of formula (IV) in an overall higher yield than the processes known from the prior art, without the formation of cis-decalin.

[0011] A first subject of the invention is therefore a compound of formula [ka] [In the formula, the bold and hatched lines indicate relative or absolute configurations] A method for preparing a compound of the formula: a) Formula [ka] [Wherein, X is vinyl, CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 is C 1-6 represents an alkyl group, R 2 is a hydrogen atom, a benzyl group, C(=O)R a Group, C(=O)OR b group, C(R c ) 2 OR d group or Si(R d ) 3 represents a group, R a is a hydrogen atom or C 1-6 is an alkyl group, R b is C 1-6 is an alkyl group, R c are each independently a hydrogen atom or C 1-2 is an alkyl group, R d is C 1-4 Either R is an alkyl group or c and R d Together, C 4-5to form an oxacycloalkyl group, in the form of any one stereoisomer or mixtures thereof of the compound of the formula [ka] [In the formula, X' is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 and R 2 has the same meaning as defined above] in the form of any one stereoisomer or a mixture thereof; b) converting the intermediate of formula (III) into a compound of formula (I); The method includes:

[0012] For the sake of clarity, expressions such as "bold and hatched lines indicate relative or absolute configuration" have the usual meaning as understood by a person skilled in the art, i.e., in the case of relative configuration, compound (I) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (4aSR,8aRS) stereoisomer, i.e. a compound having a decalin group in the relative trans configuration as shown in formula (I), and in the case of absolute configuration, compound (I) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (4aS,8R) stereoisomer.

[0013] "Oxidative cleavage" and like terms are given their normal meaning in the art, i.e., a reaction in which a carbon-carbon double bond is broken and oxidized to produce two compounds having a carbon-oxygen double bond.

[0014] The wavy line in the compounds of formula (II) and (III) indicates that the carbon chiral center carrying the bond may be of R or S relative configuration or of R or S absolute configuration, in other words, the bond may be on the same side of the ring juncture as the methyl group or the bond may be on the opposite side of the ring juncture as the methyl group.

[0015] For the sake of clarity, expressions such as "any one stereoisomer thereof or a mixture thereof" have the usual meaning as understood by the skilled artisan, i.e., it means that the compounds of formula (II) and (III) may be pure enantiomers or a mixture of enantiomers, provided, of course, that the decalin group has a trans configuration. In other words, the compounds of formula (II) and (III) have three chiral centers that can have two different stereochemistries (e.g., R or S). The compounds of formula (II) and (III) may further be in the form of pure enantiomers or in the form of a mixture of enantiomers. The compounds of formula (II) and (III) may further be in the form of pure diastereomers or in the form of a mixture of diastereomers. The compounds of formula (II) and (III) may be in racemic or scalemic form. Thus, the compounds of formula (II) and (III) may be in the form of one stereoisomer or a composition of matter that comprises or consists of various stereoisomers.

[0016] The term "alkyl" is understood to include branched and straight chain alkyl groups.

[0017] To be clear, "One R c and R d Together, C 4-5 The phrase "forms an oxacycloalkyl group..." means that the carbon atom and oxygen atom to which both groups are attached are C 4-5 It is intended to be included in the oxacycloalkyl group.

[0018] According to a particular embodiment of the invention, the compound of formula (II) has the formula [ka] wherein the bold and hatched lines and X have the meanings given in formula (I).

[0019] According to a particular embodiment of the invention, the compound of formula (II) has the formula [ka] wherein the bold and hatched lines and X have the meanings given in formula (I).

[0020] According to a particular embodiment of the invention, the compound of formula (II) may be in the form of a composition comprising a compound of formula (II') and a compound of formula (II'').

[0021] According to a particular embodiment of the invention, the compound of formula (III) has the formula [ka] wherein the bold and hatched lines and X' have the meanings given in formula (I).

[0022] According to a particular embodiment of the invention, the compound of formula (III) has the formula [ka] wherein the bold and hatched lines and X' have the meanings given in formula (I).

[0023] According to a particular embodiment of the invention, the compound of formula (III) may be in the form of a composition comprising a compound of formula (III') and a compound of formula (III'').

[0024] According to an optional embodiment of the present invention, R 1 is C 1-4 In particular, R 1 is C 1-3 Even more specifically, R 1 may be a methyl group.

[0025] According to an optional embodiment of the present invention, R a is a hydrogen atom or C 1-4In particular, R a is a hydrogen atom, C 1-3 In particular, R a may be a hydrogen atom or a methyl or ethyl group. Even more specifically, R a may be a hydrogen atom or a methyl group. Even more specifically, R a may be a hydrogen atom.

[0026] According to an optional embodiment of the present invention, R b is C 1-4 In particular, R b is C 1-3 Even more specifically, R b may be a methyl or ethyl group.

[0027] According to an optional embodiment of the present invention, one R c is a hydrogen atom or C 1-2 may be an alkyl group, and the other R c may be a hydrogen atom, i.e., R 2 is CHR c OR d In particular, one R c may be a hydrogen atom or a methyl group, and the other R c may be a hydrogen atom. Even more specifically, R c may both be hydrogen atoms, i.e., R 2 is CH 2 OR d It may be a group.

[0028] According to an optional embodiment of the present invention, R d is C 1-3 Even more specifically, R d may be a methyl or ethyl group.

[0029] According to an optional embodiment of the present invention, one R c and R d Together, C 5An oxacycloalkyl group can be formed.

[0030] According to an optional embodiment of the present invention, R 2 is a hydrogen atom or C(=O)R a In particular, R 2 may be a hydrogen atom.

[0031] According to an optional embodiment of the present invention, X is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 In particular, X may be a CHO, COOH or CH 2 Even more specifically, X may be a CH 2 It may be an OH group.

[0032] According to any embodiment of the invention, X' is CHO, COOH or CH 2 OR 2 In particular, X′ may be a COOH or CH 2 OR 2 In particular, X′ may be a COOH or CH 2 Even more specifically, X' may be a CH 2 It may be an OH group.

[0033] Non-limiting examples of compounds of formula (II) include ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methanol, ((4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methanol, ((4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methanol, (4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde, (4aS,8a S)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde, (4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde, (4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid, (4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid, (4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid , methyl or ethyl (4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate, methyl or ethyl (4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate, methyl or ethyl (4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methylformate , ((4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl formate, ((4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl formate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate, ((4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate, ((4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate, trimethyl(((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methoxy)silane, trimethyl(((4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methoxy)silane, trimethyl(((4aR,8aR)-5 ,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methoxy)silane, (4aSR,8aSR)-5-((1-ethoxyethoxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene, (4aS,8aS)-5-((1-ethoxyethoxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene, (4aR,8aR)-5-((1-ethoxyethoxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene (4aSR,8aSR)-5-((benzyloxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene, (4aS,8aS)-5-((benzyloxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene, (4aR,8aR)-5-((benzyloxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene Examples of the methyl group include (4aSR,8aSR)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene, (4aS,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene, and (4aR,8aR)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene.

[0034] According to any embodiment of the present invention, the compound of formula (II) can be prepared by methods known to those skilled in the art. In particular, the compound of formula (II) wherein X is CH 2 OR 2 R 2Compounds in which X represents a hydrogen atom or a C(═O)Me group can be produced in vitro using purified recombinant enzymes or by fermentation using host cells, such as microbial cells, by genetic engineering using the haloacid dehalogenase-like (HAD-like) hydrolase superfamily reported in WO 2018 / 220113 or WO 2019 / 229064, and then reacting with X to produce a compound in which X represents a hydrogen atom or a C(═O)Me group. 2 OR 2 is a group, R 2 When is a C(=O)Me group, the acetyltransferases disclosed in WO 2020 / 078871 can be used to convert inexpensive carbon sources (such as sugars) to the desired compound of formula (II). The advantage of using compounds of formula (II) obtained by fermentation is evident from the ready availability of starting materials with high selectivity.

[0035] According to any one of the above embodiments of the method of the invention, said method is further characterized in that the compound of formula (II) is obtained in a preceding step by contacting farnesyl pyrophosphate with at least one enzyme, such as those reported in WO 2018 / 220113 or WO 2019 / 229064, and then optionally with those reported in WO 2020 / 078871. Depending on the nature of the X group, other steps may be necessary, such as protection or oxidation, optionally followed by esterification. The aforementioned steps are well known in the art and the skilled artisan can select the optimal conditions.

[0036] Non-limiting examples of compounds of formula (III) include (4aSR,8aSR)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aSR,8aSR)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid, (4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid, methyl or ethyl (4aS R,8aSR)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate, or methyl or ethyl (4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-yl)methyl formate, ((4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-yl)methyl formate, ((4aR,8aR)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-yl -oxodecahydronaphthalen-1-yl)methyl formate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl acetate, ((4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl acetate, ((4aR,8aR)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl acetate, (4aSR,8aSR)-5,5,8a-trimethyl-1-(((trimethylsilyl)oxy)methyl)octahydro Naphthalene-2(1H)-one, (4aS,8aS)-5,5,8a-trimethyl-1-(((trimethylsilyl)oxy)methyl)octahydronaphthalene-2(1H)-one, (4aR,8aR)-5,5,8a-trimethyl-1-(((trimethylsilyl)oxy)methyl)octahydronaphthalene-2(1H)-one, (4aSR,8aSR)-1-((1-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aS,8aS)-1-((1-ethoxyethoxy)methyl)-5,5,8a-Trimethyloctahydronaphthalene-2(1H)-one, (4aR,8aR)-1-((1-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aSR,8aSR)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aS,8aS)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aR,8aR)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one Examples of the hydroxymethylene-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one include (4aSR,8aSR,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, and (4aR,8aR,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one.

[0037] According to any embodiment of the present invention, the oxidative cleavage can be carried out under conventional conditions known to those skilled in the art, i.e., for example, with ozone (a reaction also known as ozonolysis), OsO 4 / NaIO 4 , KMnO 4 / NaIO 4 , RuCl 3 / NaIO 4 , RuCl 3 / NaOCl, H 2 O 2 / NaIO 4 , or organic peroxide / NaIO 4 The oxidative cleavage may be carried out in the presence of an oxidizing agent such as . In particular, the oxidative cleavage may be ozonolysis, i.e., the compound of formula (II) is reacted with ozone. Even more particularly, the oxidative cleavage may be ozonolysis carried out under reducing conditions.

[0038] For the sake of clarity, the expression "under reducing conditions" is understood by those skilled in the art to mean that the intermediate trioxolane or hydroperoxide formed is treated with at least one reducing agent well known to those skilled in the art to obtain a compound of formula (III). Such treatment with a reducing agent can be carried out during work-up. Non-limiting examples of said reducing agents include: amines, in particular tertiary amines or pyridines, sulfites, such as alkaline sulfites (e.g. sodium or potassium sulfite, sodium bisulfite), or C 2-6 Dialkyl sulfides, such as dimethyl sulfide or methyl phenyl sulfide, sodium salt of 3,3'-thiodipropionic acid, triphenylphosphine, Zn / AcOH, Zn / AcOH / water, Na 2 S, thiourea, thiodiglycol, 3,3'-thiodipropanol, 3,3'-thiodipropionitrile, H 2 and Pd / C or Raney / Ni, P(OMe) 3 , P(OEt) 3 , P(OPh) 3 MeO(SO)OMe, MeSSMe, etc. In particular, sulfites, such as alkali sulfites (e.g. sodium or potassium sulfite, sodium bisulfite), optionally with the Na salt of 3,3'-thiodipropionic acid or C 2-6 Mention may be made of dialkyl sulfides, for example in combination with dimethyl sulfide.

[0039] When oxidative cleavage was carried out with a compound of formula (II) where X is a CHO group, the oxidative cleavage gave a compound of formula (III) where X' is a COOH group, in other words, the CHO group is oxidized under the oxidative cleavage conditions.

[0040] When oxidative cleavage was carried out with a compound of formula (II) where X is a vinyl group, the oxidative cleavage gave a mixture of compounds of formula (III) where X' is a COOH group and compounds of formula (III) where X' is a CHO group. In other words, the vinyl group is partially oxidized under the oxidative cleavage conditions. Compounds of formula (III) where X' is a CHO group give compounds of formula (III) where X' is a CHO group. a ) [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0041] Ozonolysis can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent in which the compound of formula (II) is soluble and which is currently used in ozonolysis reactions can be used for the purposes of the present invention. Non-limiting examples include: 6-10 Saturated hydrocarbon solvents, such as hexane or cyclohexane, saturated C 4-10 Ethers or esters, such as AcOEt, tetrahydrofuran, dioxane or MTBE, saturated C 2-5 Carboxylic acids, such as acidic or propionic acid, saturated C 1-5 Polar solvents, such as primary or secondary alcohols, such as isopropanol, methanol or ethanol, saturated C 2-6 Ketones, such as butanone or isobutyl methyl ketone, C 1-3 Mention may be made of chlorinated alkanes, such as chloroform or dichloromethane, or mixtures thereof. The exact choice of solvent depends on the required compound of formula (II) and the reaction rate. Those skilled in the art are fully capable of choosing the most convenient solvent in each case to optimize the ozonolysis reaction.

[0042] The solvent can be added to the reaction medium in a wide range of concentrations, non-limiting examples being amounts of solvent ranging from 50% to 500% w / w relative to the amount of compound of formula (II) used.

[0043] The temperature at which the oxidation can be carried out is in the range of −100° C. to 40° C., in particular in the range of −80° C. to 20° C., and even more particularly in the range of −40° C. to 0° C. Of course, the skilled person can select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion.

[0044] Ozone can be added to the reaction medium in a wide range of concentrations. Non-limiting examples include ozone concentration values ​​ranging from 0.8 molar equivalents to 3 molar equivalents relative to the amount of compound of formula (II). Preferably, the ozone concentration is between 1.0 molar equivalents and 1.2 molar equivalents. It goes without saying that the optimum concentration of ozone depends on the nature of the compound of formula (II), the desired conversion and the desired reaction time, as known to those skilled in the art.

[0045] The reducing agent can be added to the reaction medium in a wide range of concentrations. As a non-limiting example, values ​​in the range of 0.5 molar equivalents to 10 molar equivalents relative to the amount of the compound of formula (II) can be mentioned as the reducing agent concentration value. Preferably, the reducing agent concentration is 0.8 molar equivalents to 10 molar equivalents. Even more preferably, the reducing agent concentration is 2.0 molar equivalents to 5 molar equivalents. It goes without saying that the optimal concentration of the reducing agent depends on the nature of the reducing agent, the nature of the compound of formula (II), the desired conversion and the desired reaction time, as known to those skilled in the art.

[0046] The conditions used to convert the intermediate of formula (III) to a compound of formula (I) depend on the nature of the X' group.

[0047] According to a particular embodiment of the invention, X′ is CH 2 OR 2 When R is a group, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a retro-aldol reaction. 2If R is not a hydrogen atom, deprotection is carried out before the retroaldol. 2 It depends on the nature of the group. A person skilled in the art will be able to select the best conditions. For example, R 2 is C(=O)R a R a is a hydrogen atom or C 1-6 When X' is an alkyl group, the compound of formula (III) is 2 Deprotection to form what is an OH group can be carried out under conventional conditions known to those skilled in the art, for example, water and acid, preferably H 2 SO 4 The reaction may be carried out in the presence of an acid having a pH in the range of 1-2, such as pTsOH, oxalic acid or phosphoric acid, or in the presence of an enzyme such as lipase.

[0048] According to a particular embodiment of the invention, the retro-aldol reaction is a thermal retro-aldol reaction.

[0049] The temperature at which the retro-aldol reaction can be carried out is in the range of 450° C. to 550° C., in particular in the range of 49 ...30° C., and even more particularly in the range of 490° C. to 510° C. Of course, the skilled person can select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion.

[0050] The retro-aldol reaction can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. In particular, the retro-aldol reaction is carried out in the presence of a solvent having a boiling point of 65° C. or higher, even 75° C. or higher, even 80° C. or higher, even 110° C. or higher, or even 130° C. or higher. Non-limiting examples of suitable solvents include alcohol solvents, such as methanol, ethanol, 1-propanol, isopropanol, 1-hexanol, 1-octanol, 1-butanol, 1-pentanol, 4-methylpentan-2-ol, 2-methyl-1-pentanol, 1-heptanol, 2-octyl alcohol, cyclohexanol or mixtures thereof, C 6-12 Examples of suitable solvents include aromatic solvents such as toluene, xylene or mixtures thereof, hydrocarbon solvents such as n-heptane, n-decane, n-dodecane, n-nonane, cyclohexane or mixtures thereof, ether solvents such as diisobutyl ether, di-n-butyl ether or mixtures thereof, solvents containing ketone functional groups such as 4-methyl-2-pentanone MIBK, 2-octanone, cyclohexanonone, 2-heptanone, 6-methyl-2-heptanone, 6-methyl-5-hepten-2-one, isophorone or mixtures thereof, solvents containing aldehyde functional groups such as hexanal, octanal or mixtures thereof. The choice of solvent depends on the nature of the substrate, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0051] The retro-aldol reaction can be carried out in a batch or continuous mode.

[0052] Unexpectedly, the thermal retro-aldol reaction allows the formation of less by-products. The conditions reported in the prior art for such transformations, such as the industrially inapplicable Jones oxidation, do not allow the compound of formula (I) to be obtained in high yield. According to a particular embodiment of the process of the present invention, the compound of formula (VII) [ka] At most, only 20% of the undesired rejected products are formed.

[0053] According to a particular embodiment of the invention, X' is COOH or C(=O)OR 1 is a group, R 1 The conversion of the intermediate of formula (III) to the compound of formula (I) comprises a decarboxylation reaction, where X′ has the same meaning as defined above. The decarboxylation reaction can be carried out under conventional conditions known to those skilled in the art, i.e. in the presence of a base such as an alkali metal hydroxide, e.g. NaOH or KOH, or in the presence of an acid such as a Brønsted or Lewis acid. In particular, the decarboxylation can be carried out when X′ is C(═O)OR 1 is a group, R 1 has the same meaning as defined above. Decarboxylation is well known and has been widely reported in the prior art. Thus, a person skilled in the art will recognize that a compound of formula (III) in which X' is COOH or C(=O)OR is a carboxyl group. 1 is a group, R 1 has the same meaning as defined above to the compound of formula (I). As a non-limiting example, the decarboxylation reaction can be carried out under the conditions reported in WO 2012 / 069647. Specific non-limiting examples of Bronsted or Lewis acids are dilute sulfuric acid, paratoluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, methanedisulfonic acid, methanetrisulfonic acid, 2,4 dinitrobenzenesulfonic acid, dilute HCl and Al 2 O 3 The compound may be selected from the group consisting of:

[0054] The acid or base can be added to the reaction medium of the method of the invention in a wide range of concentrations. As non-limiting examples, values ​​of the acid or base concentration can be mentioned in the range of about 1 to about 20 mol% relative to the amount of substrate, preferably 5 to about 10 mol% relative to the amount of substrate. As the skilled person knows, the optimal concentration of the acid or base depends on the nature of the acid or base, the nature of the substrate, the reaction temperature and the desired reaction time.

[0055] According to any one of the embodiments of the present invention, the decarboxylation reaction can be carried out at a temperature of 20° C. to 80° C. In particular, the temperature ranges from 20° C. to 60° C. Of course, the skilled person can also select the preferred temperature according to the melting and boiling points of the starting and final products and the desired reaction time or conversion rate.

[0056] The decarboxylation reaction can be carried out in the presence or absence of a solvent. Where a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. Non-limiting examples include C 6-12 Mention may be made of aromatic solvents such as toluene, xylene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof, alcoholic solvents such as methanol, ethanol or mixtures thereof, hydrocarbon solvents such as cyclohexane or heptane, ethyl acetate or ethereal solvents such as dioxane, methyltetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of solvent depends on the nature of the substrate and / or the base or acid, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0057] According to a particular embodiment of the invention, when X' is a CHO group, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a decarbonylation reaction or alternatively an oxidation reaction followed by a decarboxylation reaction. The decarbonylation reaction can be carried out under conventional conditions known to those skilled in the art, i.e. in the presence of an alkali metal hydroxide, e.g. NaOH or KOH; and RCOOM, where R is a C1-8 alkyl group and M is an alkali metal, e.g. KOAc. The oxidation reaction can be carried out under conventional conditions known to those skilled in the art, such as under Jones conditions. The decarboxylation reaction can be carried out under the conditions reported above.

[0058] According to an optional embodiment of the present invention, the compound of formula (I) is [ka] [wherein the bold and hatched lines indicate relative or absolute configuration]. The conversion of compounds of formula (I) to compounds of formula (IV) has been widely reported in the prior art, such as Journal of Chemical Research, Synopses (1998), (1), 36-37).

[0059] Compounds of formula (II), where X is a vinyl group, are novel compounds and offer many advantages as explained above and illustrated in the examples.

[0060] Another subject of the invention is therefore a compound of formula [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0061] Compounds of formula (III), in which X' is a COOH group, are novel compounds and offer many advantages as explained above and illustrated in the examples.

[0062] Another subject of the invention is therefore a compound of formula [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0063] The ozonolysis of the compounds of formula (II) gives ozonide intermediates which are novel compounds and which exhibit many advantages as explained above and shown in the examples. Another subject of the present invention is therefore the preparation of compounds of formula [ka] [In the formula, the bold and hatched lines indicate the relative or absolute configuration, and X is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 is C 1-6 represents an alkyl group, R 2 is a hydrogen atom, a benzyl group, C(=O)R a Group, C(=O)OR b group, C(R c ) 2 OR d group or Si(R d ) 3 represents a group, R a is a hydrogen atom or C 1-6 is an alkyl group, R b is C 1-6 is an alkyl group, R c are each independently a hydrogen atom or C 1-2 is an alkyl group, R d is C 1-4 Either R is an alkyl group or c and R d Together, C 4-5 The compound may be in the form of any one of the stereoisomers or a mixture thereof, wherein the compound forms an oxacycloalkyl group.

[0064] In one embodiment of the present invention, the compound of formula (II) used in the presently claimed method is obtained by contacting farnesyl pyrophosphate with at least one enzyme.

[0065] In some embodiments of the presently claimed methods, an enzyme is used to produce a compound of formula (II). For example, a compound of formula (II) in which X is CH 2 OR 2 R 2 represents a hydrogen atom or a C(═O)Me group, the haloacid dehalogenase-like (HAD-like) hydrolase superfamily reported in WO 2018 / 220113 or WO 2019 / 229064 is used, and then X is CH 2 OR 2 R 2 When is a C(=O)Me group, it can be produced using the acetyltransferases disclosed in WO 2020 / 078871.

[0066] In some embodiments of the presently claimed methods, an enzyme is used to produce the compound of formula (II).

[0067] The process for preparing the compounds of formula (II) can be carried out in vitro or in vivo, as described in more detail below.

[0068] When the method is carried out in vitro, the enzyme used can be obtained by extraction from any organism expressing said enzyme using standard enzyme extraction techniques. If the host organism is a unicellular organism or cell, the enzyme can simply be recovered from the culture medium, for example by centrifugation, optionally followed by a washing step and resuspension in an appropriate buffer. If the organism or cell accumulates the enzyme intracellularly, the enzyme can be obtained by disrupting or lysing the cells and further extracting the enzyme from the cell lysate.

[0069] In the in vitro method, the enzyme can be provided in isolated form or as part of a protein extract and is suspended in a buffer at an optimal pH. If appropriate, salts, DTT, NADPH, NADH, FAD, FMN and other types of enzyme cofactors may be added to optimize the enzyme activity. The precursor compound is then added to the reaction mixture and incubated at an optimal temperature, for example 15-40°C, preferably 25-35°C, more preferably 30°C. After incubation, the compound of formula (II) produced can be isolated from the incubated solution by standard isolation techniques such as solvent extraction or distillation, optionally after removing the enzyme from the solution.

[0070] According to another preferred embodiment, the method for preparing a compound of formula (II) is carried out in vivo, in which case the method comprises culturing a non-human host organism or cell transformed to express the enzyme in the presence of the starting compound to be converted to a compound of formula (II) under conditions conducive to the enzymatic reaction.

[0071] In one embodiment, when a host cell is used or when the host organism is a microorganism, the compound to be converted can be added to the culture medium of said cell or microorganism, the starting compound permeating the membrane of the cell or microorganism and therefore available to react with the enzyme expressed by said host cell or microorganism.

[0072] Carrying out the method in vivo is particularly advantageous since it can be carried out without prior isolation of the enzyme: the reaction takes place directly in an organism or cell that has been transformed to express the enzyme.

[0073] To practice the invention in vivo, a host organism or cell is cultured under conditions conducive to the production of a compound of formula (II). Such conditions are any conditions conducive to the growth of the host organism or cell. Preferably, such conditions are designed to allow optimal growth of the host organism or cell. When the host is a unicellular organism, conditions conducive to the production of a compound of formula (II) can include the addition of appropriate cofactors to the host medium. Additionally, the culture medium can be selected to maximize synthesis.

[0074] Optimal culture conditions are known to those of skill in the art and are not a part of the present invention.

[0075] In a more preferred embodiment, the organism used to carry out the method of the invention in vivo is a microorganism. Any microorganism can be used, but according to an even more preferred embodiment, the microorganism is a bacterium or a fungus. Preferably, the fungus is a yeast. Most preferably, the bacterium is E. coli and the yeast is Saccharomyces cerevisiae.

[0076] Another object of the present invention is the preparation of compounds of formula (I) and (IV) by the use of the compound of formula (I) [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0077] Another object of the present invention is the preparation of compounds of formula (I) and (IV) by the use of the compound of formula (I) [ka] [In the formula, the bold and hatched lines indicate the relative or absolute configuration, and X is CHO, COOH, C(=O)OR 1 or CH 2 OR 2 represents a group, R 1 is C 1-6 represents an alkyl group, R2 is a hydrogen atom, a benzyl group, C(=O)R a Group, C(=O)OR b group, C(R c ) 2 OR d group or Si(R d ) 3 represents a group, R a is a hydrogen atom or C 1-6 is an alkyl group, R b is C 1-6 is an alkyl group, R c are each independently a hydrogen atom or C 1-2 is an alkyl group, R d is C 1-4 Either R is an alkyl group or c and R d Together, C 4-5 The use of any one of the stereoisomers or mixtures thereof of the compounds of formula (I) forming an oxacycloalkyl group.

[0078] Another object of the present invention is the preparation of compounds of formula (I) and (IV) by the use of the compound of formula (I) [ka] wherein the bold and hatched lines indicate relative or absolute configuration.

[0079] Typical modes for carrying out the method of the invention are reported below in the Examples. EXAMPLES

[0080] The invention will now be described in further detail by the following examples, in which abbreviations have their usual meaning in the art and temperatures are given in degrees Celsius (°C). Preparation of precatalyst and ligand solutions was carried out using standard Schlenk techniques under an inert atmosphere (argon). Solvents were routinely dried and distilled under an argon atmosphere. NMR spectra were recorded on a Bruker AV 300, AV 400, or AV 500 MHz spectrometer at 20°C. Chemical shifts were recorded relative to the solvent signals (chloroform, δH = 7.26 ppm, δ C ==77.0 ppm). Signal assignments are reported as 1 H, 1 H-COSY, -NOESY, 13 C. 1 The results were confirmed by recording H-HSQC and -HMBC experiments. Gas chromatography was performed on an Agilent 7890 A series equipped with an HP5 column (30 m×0.25 mm inner diameter, 0.25 μm film) and tetradecane was used as the internal standard.

[0081] [Example 1: Production of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate] 36.0 g (136.2 mmol) of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate was dissolved in 480 mL of MeOH in the presence of 38.3 g (578.7 mmol, 4.3 eq) of KOH in a 1 L flask under stirring. After 2 h, complete conversion of the starting material was observed. Part of the solvent was evaporated under reduced pressure (45° C., 15 mbar) and 1.5 L of diethyl ether and 500 mL of water were added.

[0082] The aqueous phase was separated and the organic phase was washed twice with 500 mL of water and once with 500 mL of saturated aqueous NaCl. 2 SO 4 The mixture was dried over low heat and the solvent was evaporated under reduced pressure (45 °C, 500-3 mbar). 100 mL of pentane was added and the solvent was evaporated under reduced pressure (45 °C, 500-3 mbar). A white solid (29.7 g ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol, 133.7 mmol, 98% yield) was obtained.

[0083] 1 H and 13C NMR spectral data are as reported in M. Goehl, K. Seifert, Eur. J. Org. Chem. 2014, 6975-6982.

[0084] [Example 2: Production of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methanol] 15.61 g (70.2 mmol) of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol, (0.523 g (7.02 mmol) of KCl, 2.84 g (7.02 mmol) of Fe(NO 3 ) 3 9H 2 O and 1.097 g (7.02 mmol) of TEMPO were dissolved in 150 mL of toluene. Air was bubbled through the solution and the mixture was stirred for 25.5 h. An additional amount of catalyst (0.523 g (7.02 mmol) of KCl, 2.84 g (7.02 mmol) of Fe(NO 3 ) 3 9H 2 2H2O and 1.097 g (7.02 mmol) of TEMPO were added, air was bubbled through the solution, and the mixture was stirred for 21 h. 50 mL of water and 75 mL of Et 2 After adding O, the mixture was stirred for 10 min. The organic phase was separated and washed with 50 mL of water and 50 mL of saturated aqueous NaCl. 2 SO 4 After drying over 100° C. and filtration, the solvent was evaporated under reduced pressure (crude 18.73 g). The product was purified by column chromatography (80 g SiO 2 , Et 2The mixture was purified with 1:9 hexane / cyclohexane (1:9). 13.7 g of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde was obtained as an orange oil (GC purity 98.8%, yield 88%). Only 0.3 g (1.8%) of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid was isolated.

[0085] 1 H and 13 C NMR spectral data is the same as reported in Hua, D.H.; Huang, X.; Chen, Y.; Battina, S.K.; Tamura, M.; Noh, S.K.; Koo, S.I.; Namatame, I.; Tomada, H.; Perchellet, E.M.; Perchellet, J.-P.J. Org. Chem. 2004, 69, 6065-6078.

[0086] [Example 3: Production of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid from (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde] 20.0 g (69.7 mmol) of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde, 13.08 g (218 mmol) of AcOH, 28.5 g (386 mmol) of isoamylene were added to 50 mL of EtOAc. 12.31 g (80% purity, 109 mmol) of NaClO in 60 mL of water. 2 The mixture was slowly added under stirring while maintaining the temperature at 25-38°C. After the addition was complete, the mixture was heated at 40°C (oil bath) for 30 minutes. After cooling to room temperature, 120 mL of 10% Na 2 S 2 O 3 Aqueous 5% NaOH was added and stirring was continued for 15 min. Then, 5% aqueous NaOH was added until a slightly basic pH was achieved. After stirring for 10 min, a standard acid / base extraction (Et2 After evaporation of the solvent under reduced pressure, 19.9 g of a crystalline solid was obtained. The product was purified by column chromatography (300 g SiO 2 , AcOEt / cyclohexane 2 / 8) to isolate 17.4 g of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid as a white solid (purity 99.1%, yield 80%).

[0087] CDCl 3 In 1 H-NMR and 13 The C-NMR analysis results were consistent with the data in the literature (T. Laube, J. Schroeder, R. Stehle, K. Seifert, Tetrahedron 2002, 58, 4299-4309).

[0088] [ka]

[0089] (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid can also be prepared from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-yl)methanol using the Jones oxidation (72% yield).

[0090] [Example 4: Preparation of methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate from (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid] 2 g (8.46 mmol) of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid was heated to reflux with stirring in the presence of 18 g (200 mmol) of dimethyl carbonate (boiling point of dimethyl carbonate 92° C.) and 1.288 g (8.46 mmol) of DBU. After 9 h, complete conversion was achieved and the excess dimethyl carbonate was evaporated under reduced pressure. 50 mL of AcOEt was added and the solution was washed twice with 5% aqueous HCl and once with saturated aqueous NaCl. The organic phase was washed with Na 2 SO 4 The mixture was dried over ice and the solvent was evaporated under reduced pressure (2.08 g of methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate, 98.5% purity, 97% yield). No further purification was necessary.

[0091] CDCl 3 In 1 H-NMR and 13 The C-NMR analysis results were consistent with the data in the literature (T. Laube, J. Schroeder, R. Stehle, K. Seifert, Tetrahedron 2002, 58, 4299-4309).

[0092] [ka]

[0093] Methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate was reacted with MeI and K in acetone. 2 CO 3 It can also be prepared from methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate in the presence of (4 h, 40° C., 91% yield).

[0094] [Example 5: Preparation of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol] 13.0 g (98.1% purity, 57.4 mmol) of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol was dissolved in 600 mL of MeOH in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled into it under stirring until complete conversion of the starting material was observed by GC (KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 7.13 g (114.7 mmol, 2 eq) of MeOH was dissolved in 600 mL of MeOH. The mixture was cooled to 0° C. and ozone was bubbled into it under stirring until complete conversion of the starting material was observed by GC (KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 2 S was added under stirring at 0° C. The cooling was removed after 1.5 h and the mixture was stirred at room temperature overnight. The KI test was slightly positive, so 15.0 g (57.4 mmol, 1 eq) of PPh 3 After 15 min, the KI test was negative and GC showed 96.7% product. The mixture was filtered and the solvent was evaporated under reduced pressure (Rotavap in fume hood, 45 °C, 50-5 mbar). Some pentane and dichloromethane were added and evaporated under reduced pressure (32.9 g crude). The crude (mixed with a small amount of dichloromethane) was purified by flash chromatography (2 × 330 g SiO 2 The crude product was purified with eluents cyclohexane 7 / EtOAc 3), yielding 12.92 g (98.6% purity, 56.8 mmol, 99.0% yield) of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one as a white solid.

[0095] CDCl 3 In 1 H-NMR and 13The C-NMR analysis results were consistent with the data in the literature (Furuichi, N.; Hata, T.; Soetjipto, H.; Kato, M.; Katsumura, S. Tetrahedron 2001, 57, 8425-8442).

[0096] [ka]

[0097] The reduction of the ozonide can also be carried out with the monosodium salt of 3,3'-thiodipropionic acid (2 eq, 99% yield).

[0098] The reduction of the ozonide can also be carried out with thiodiglycol (2 eq, 99% yield).

[0099] The reduction of the ozonide can also be carried out with thiourea (0.5 eq, 95% yield).

[0100] Similar yields were obtained with AcOH.

[0101] Depending on the reducing reagent and the pH before solvent evaporation, up to 6% of (1S,4aS,8aS)-1-((hydroxymethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one could be identified by NMR spectroscopy (or GC after silylation). The content of (1S,4aS,8aS)-1-((hydroxymethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one in (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one did not affect the selectivity and yield of the thermal retro-aldol reaction to (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one.

[0102] (1S,4aS,8aS)-1-((hydroxymethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one [ka]

[0103] NMR signals of silylated (1S,4aS,8aS)-1-((hydroxymethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: (1S,4aS,8aS)-5,5,8a-trimethyl-1-((((trimethylsilyl)oxy)methoxy)methyl)octahydronaphthalen-2(1H)-one [ka]

[0104] Example 6: Preparation of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol with isolation of intermediate ozonide 1.00 g of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol (4.50 mmol) was dissolved in 90 mL of EtOAc in an ozonolysis flask. The mixture was cooled to 0° C. and oxygen was bubbled through the mixture with stirring for 10 min. Ozone was then bubbled through the solution at 0° C. for 7 min. Finally, oxygen and nitrogen were bubbled through the mixture at 0° C. for 10 min. The intermediate (((1S,4aS,8aS)-5,5,8a-trimethyloctahydro-1H-spiro[naphthalene-2,3′-[1,2,4]trioxolan]-1-yl)methanol) was analyzed by NMR spectroscopy.

[0105] [ka]

[0106] This intermediate was mixed with 2.36 g (8.99 mmol, 2 eq) of PPh 3was added and the mixture was allowed to warm slowly to room temperature (2 h). After stirring overnight and washing with saturated aqueous NaCl, the mixture was 2 SO 4 The crude was purified by flash chromatography (100 g SiO 2 , eluent cyclohexane 7 / EtOAc 3), affording 0.969 g (4.32 mmol, 96% yield) of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one as a white solid.

[0107] CH 2 Cl 2 However, the same yield (>95%) was obtained.

[0108] [Example 7: Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one from (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one] 2 g (purity 97.8%, 8.72 mmol) of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was dissolved in 26 mL of 1-octanol. 2 The mixture was slowly (26 mL / h) added to a heated pyrolysis column (23 x 2 cm, pyrolysis oven at 500 °C) under a constant current (flow). The column was packed with 56 g of glass beads, and a water condenser and a 100 mL flask were connected below the pyrolysis column. After the end of the addition (1 h), the oven was cooled. When the oven temperature reached 50 °C, the column was washed twice with 5 mL of cyclohexane. The cyclohexane was evaporated under reduced pressure and the 1-octanol was distilled off under reduced pressure (Vigreux column). The crude product (GC 89%) was purified by flash chromatography (120 g SiO 2The crude product was purified with eluent cyclohexane 8 / EtOAc 2), yielding 1376 mg (7.08 mmol, 81.2% yield) (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one as a white solid.

[0109] CDCl 3 In 1 H-NMR and 13 The C-NMR analysis results are shown in the literature (A. Gautier, C. Vial, C. Morel, M. Lander, F. Naef, Helv. Chim. Acta, 1987, 70, 2039 and I. Jabin, G. Revial, K. Melloul, M. Pfau, Tetrahedron: Asymmetry 1997, 8, 1101-1109).

[0110] [ka]

[0111] [Example 8: Production of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one and (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid from (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde] 3.92 g (98.8% purity, 17.81 mmol) of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carbaldehyde was dissolved in 120 mL of EtOAc in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled into it under stirring until complete conversion of the starting material was observed by GC (30 min, KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 10.5 g (40.1 mmol, 2.25 eq) of PPh 3The cooling was removed after 1.5 hours and the mixture was stirred at room temperature overnight (KI test was negative). The mixture was washed twice with 2.5% aqueous NaOH. The organic phase was washed with saturated aqueous NaCl and Na 2 SO 4 The crude was purified by flash chromatography (120 g SiO 2 The crude product was purified with eluents cyclohexane 8 / EtOAc 2), yielding 368 mg (1.89 mmol, 11% yield) of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one as a white solid.

[0112] To the combined aqueous phase (2.5% aqueous NaOH), 5% aqueous HCl was slowly added until a pH of 4 was reached. The aqueous phase was extracted twice with 100 mL of EtOAc. The combined organic phase was washed with saturated aqueous NaCl and Na 2 SO 4 The crude product was purified by flash chromatography (220 g of SiO 2 The mixture was purified with eluents cyclohexane / EtOAc (8:8) to cyclohexane / EtOAc (6:4) to give 2626 mg (11.02 mmol, 62% yield) of (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid as a white solid.

[0113] (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid: [ka]

[0114] (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid can be converted to (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one in the presence of dilute sulfuric acid (and heating). Quantitative yields were obtained.

[0115] [Example 9: Production of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one and (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid from (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid] 0.617 g (2.613 mmol) of (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid was dissolved in 30 mL of MeOH in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled into it under stirring until complete conversion of the starting material was observed by GC (10 min, KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 0.399 g (6.414 mmol) of MeOH was dissolved in 30 mL of MeOH in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled into it under stirring until complete conversion of the starting material was observed by GC (10 min, KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 2 S was added at 0° C. under stirring. Cooling was removed after 1.5 h and the mixture was stirred at room temperature overnight (KI test was negative). The solvent was evaporated under reduced pressure (in a fume hood). The crude was dissolved in diethyl ether and washed with 5% aqueous HCl, water (3 times) and saturated aqueous NaCl. The aqueous phase was re-extracted with diethyl ether and the combined organic phases were washed with 5% aqueous NaOH. A precipitate was observed (water insoluble, Na salt of (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid). The suspension was extracted twice with diethyl ether. The organic phase was separated and the suspension was treated with 5% aqueous sulfuric acid. CO was added while stirring at room temperature. 2 The formation of was observed. After 20 min, the mixture was heated at 50° C. for 10 min. After cooling to room temperature, 0.340 mg (1.75 mmol, 67% yield) of an insoluble white solid ((4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one) could be separated from the aqueous phase.

[0116] [Example 10: Preparation of methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate from methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate] 13.66 g (54.6 mmol) of methyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate (54.27 mmol) was dissolved in 350 mL of MeOH in an ozonolysis flask. The mixture was cooled to 0° C. and ozone was bubbled through the solution with stirring for 3 h. Oxygen was then bubbled through at 0° C. for 15 min. Dimethyl sulfide (8.53 g, 137 mmol) was added quickly and the mixture was stirred at 0° C. for 1.5 h under nitrogen bubbling (to the solution). The reaction was then stirred at room temperature for 18.5 h. After KI control (which must be negative), the solvent was evaporated using a Rotavap in a fume hood at reduced pressure (40° C.). 13.34 g of methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate (52.6 mmol, 96% yield) was obtained, which was used in the next step without further purification.

[0117] CDCl 3 In 1 H-NMR and 13 The C-NMR analysis results were consistent with the data in the literature (Y. Tanada, K. Mori, Eur. J. Org. Chem. 2003, 848-854).

[0118] [Example 11: Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one from methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate] 13.34 g of methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate (52.6 mmol, from the previous step) was added to a mixture of 39.5 g (705 mmol) of KOH, 78 mL of water, and 78 mL of EtOH (flask with reflux condenser). After heating at 120 °C (oil bath) for 26 h, the mixture was cooled to room temperature. The reaction was added to ice water and 500 mL of EtOH were added. 2 The combined organic phase was washed with 500 mL of water, 500 mL of saturated aqueous NaCl solution, and the organic phase was extracted with Na 2 SO 4 After evaporation of the solvent under reduced pressure, 11.02 g (GC purity 94.5%) of crude product was obtained. This product was purified by column chromatography (330 g SiO 2 The mixture was purified with 13 / 87 EtOAc / cyclohexane -> 3 / 7 EtOAc / cyclohexane to give 8.66 g (44.58 mmol, 85% yield) of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one as a white solid.

[0119] The preparation of (-)-polywood ((2S,4aS,8aR)-5,5,8a-trimethyldecahydronaphthalen-2-yl acetate) from (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one is described in the literature: Cortes, Manuel; Moreno, Luis; Lopez, Jose Journal of Chemical Research, Synopses (1998), (1), 36-37).

[0120] Example 12: Preparation of compound of formula (II) starting from ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methanol a) Preparation of ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl formate 2eq of Ac 2O, 2 eq formic acid, 1 h, 50 °C, toluene, 97% yield [ka]

[0121] b) Preparation of trimethyl(((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methoxy)silane 3 eq TMSCl, 3 eq NEt 3 , yield 83% [ka]

[0122] c) Preparation of (4aS,5S,8aS)-5-((1-ethoxyethoxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene 3eq ethyl vinyl ether, 0.11eq CF 3 COOH, 30℃, 2.5h, yield 90% [ka]

[0123] d) Preparation of (4aS,5S,8aS)-5-((benzyloxy)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalene 1.05eq benzyl chloride, 1.05eq KOtBu, 43h, rt, THF, 90% yield [ka]

[0124] [Example 13: Preparation of compound of formula (III) by oxidative cleavage of compound of formula (II)] The starting material (38.94 mmol) prepared in Example 12 was dissolved in 100 mL of solvent in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled inside under stirring until complete conversion of the starting material was observed by GC (50 min, positive KI test). Oxygen (5 min) and nitrogen (5 min) were then bubbled into the mixture. 20.43 g (77.88 mmol, 2 eq) of PPh 3 Cooling was removed after 1.5 h and the mixture was stirred at room temperature for 3 h (KI test was negative). When MeOH was used as solvent, the solvent was evaporated under reduced pressure (Rotavap in fume hood) and 100 mL of EtOAc was added. The organic phase was washed with saturated NaHCO 3 It was washed with aqueous solution (50 mL) and water (50 mL). The solvent was evaporated under reduced pressure (Rotavap in a fume hood). The crude was purified by flash chromatography (triphenylphosphine oxide can be removed by crystallization with pentane (50 mL) prior to flash chromatography).

[0125] a) ((1S,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl formate (ozonolysis in MeOH, 78% yield) [ka]

[0126] b) ((1S,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl acetate (ozonolysis in MeOH, 69% yield) [ka]

[0127] c) (1S,4aS,8aS)-5,5,8a-trimethyl-1-(((trimethylsilyl)oxy)methyl)octahydronaphthalen-2(1H)-one (ozonolysis in EtOAc, 77% yield) [ka]

[0128] d) (1S,4aS,8aS)-1-((1-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one (ozonolysis in EtOAc, 88% yield) [ka]

[0129] e) (1S,4aS,8aS)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one (ozonolysis in MeOH, 78% yield) [ka]

[0130] [Example 14: Preparation of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one] In most cases, H 2 SO 4 or KHCO 3 A standard protocol using the method described above was used.

[0131] To 0.394 mmol of the starting material prepared in Example 13 in 400 mg of MeOH, 155 mg of 5% H 2 SO 4 Aqueous solution (0.2 eq) was added. The mixture was stirred at room temperature until complete deprotection to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was observed (GC analysis using silylation). 753 mg of 10% K 2 CO 3 Aqueous solution (1.4 eq) was added and MeOH was evaporated under reduced pressure. 5 g cyclohexane was added and the mixture was washed twice with 5 g water. The solvent was evaporated under reduced pressure (GC analysis with silylation).

[0132] or To 0.394 mmol of the starting material prepared in Example 13 in 400 mg of MeOH, 8 mg of KHCO 3 (0.2 eq). The mixture was stirred at room temperature until complete deprotection to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was observed (GC analysis with silylation). MeOH was evaporated under reduced pressure. 5 g cyclohexane was added and the mixture was washed twice with 5 g water. The solvent was evaporated under reduced pressure (GC analysis with silylation).

[0133] a) ((1S,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl formate to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: 0.2 eq H in water / MeOH 2 SO 4 After 4 h at room temperature, 100% conversion, 97.6% (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one by GC analysis (using silylation).

[0134] 0.2 eq KHCO in MeOH 3 After 3.5 h at room temperature, 99% conversion, 97.4% (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one by GC analysis (using silylation).

[0135] b) ((1S,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalen-1-yl)methyl acetate to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one and (1R,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: 0.2 eq H in water / MeOH 2 SO 4 , 3d at room temperature, 99% conversion, GC analysis (using silylation) gave 59.1% (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one and 15.7% (1R,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one.

[0136] c) (1S,4aS,8aS)-5,5,8a-trimethyl-1-(((trimethylsilyl)oxy)methyl)octahydronaphthalen-2(1H)-one to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: 0.2 eq H in water / MeOH 2 SO 4 After 2 h at room temperature, 100% conversion, 97.5% (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one by GC analysis (using silylation).

[0137] d) (1S,4aS,8aS)-1-((1-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: 0.2 eq H in water / MeOH 2 SO 4 After 2 h at room temperature, 99% conversion, 94.2% (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one by GC analysis (using silylation).

[0138] e) (1S,4aS,8aS)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one to (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one: 300 mg of (1S,4aS,8aS)-1-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was reacted in the presence of 100 mg of 10% palladium on carbon in 10 mL of EtOH in an autoclave (20 psi H 2 for 4 h). Complete conversion was observed (98% selectivity for (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one). The mixture was filtered through a pad of Celite® and the solvent was evaporated under reduced pressure.

[0139] [Example 15: Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one from (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one] A separate Inox tube with heating (pyrolysis oven, 3 cm x 50 cm) was connected to the condenser at the top of the column and the evaporator system at the bottom. The column was heated to 530 °C (internal) and the evaporator to 240 °C over 1 h. The whole system was set to vacuum (10 mbar). A mixture of 8.68 g (38.57 mmol) of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one and 44 mL of 1-hexanol was added to the evaporator by syringe pump (115 g / h), the mixture was evaporated at 240 °C and distilled through the Inox tube (internal 530 °C) and the product mixture (selectivity 96% by GC) was collected in a flask with a condenser. The evaporator and column were purged with 1-hexanol (50 g) and heptane (90 g). Work-up (saturated NaHCO 3After aqueous and water washings), solvent evaporation and distillation, (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was obtained in 97% selectivity (7.14 g, 36.75 mmol, 95% isolated yield).

[0140] [Example 16: Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one from (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one (solvent test)] General Protocol 400 mg (purity 95%, 1.69 mmol) of (1S,4aS,8aS)-1-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was dissolved in 6 mL of solvent. 2 The mixture was slowly (26 mL / h) added to a pyrolysis column (23 x 2 cm, pyrolysis oven at 500 °C) heated under a constant current (flow). The column was packed with 56 g of glass beads, and a water-cooled condenser and a 25 mL flask were connected to the bottom of the pyrolysis column. GC analysis of a drop of the mixture after 4 min gave a selectivity for the formation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one.

[0141] 1-Octanol: 89% product selectivity (GC), complete conversion (GC) 4-Methyl-2-pentanone: 81% product selectivity (GC), complete conversion (GC) 1-Hexanol: 87% product selectivity (GC), complete conversion (GC) 1-Butanol: 83% product selectivity (GC), complete conversion (GC) 1-Propanol: 92% product selectivity, complete conversion (GC) Ethanol: 89% product selectivity (GC), complete conversion (GC) Methanol: 83% product selectivity (GC after 14 min) 1-Hexenal: 80% product selectivity (GC), complete conversion (GC) Dibutyl ether: 84% product selectivity (GC), complete conversion (GC) Cyclohexanone: 87% product selectivity (GC), complete conversion (GC) p-Xylene: 87% product selectivity (GC), complete conversion (GC).

[0142] [Example 17: Preparation of (4aS,5S,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene] The acetate (2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl acetate) or tosylate (2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl 4-methylbenzenesulfonate) of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol was prepared according to the literature (G. Ohloff, W. Giersch Croatica Chem. Acta 1985, 58, It can be prepared from (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2,1-b]furan-2(1H)-one according to the procedure described above.

[0143] Elimination of the acetate (pyrolysis at 500°C) or tosylate (DBU) afforded (4aS,5S,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene as a yellow liquid.

[0144] [ka]

[0145] Intermediates for the production of (4aS,5S,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene: (2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl acetate) [ka]

[0146] (2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl 4-methylbenzenesulfonate) [ka]

[0147] [Example 18: Production of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one and (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid from (4aS,5S,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene] 1 g (4.58 mmol) of (4aS,5S,8aS)-1,1,4a-trimethyl-6-methylene-5-vinyldecahydronaphthalene was dissolved in 100 mL of EtOAc in an ozonolysis reactor. The mixture was cooled to 0° C. and ozone was bubbled inside under stirring until complete conversion of the starting material was observed by GC (KI test positive). Oxygen (10 min) and nitrogen (10 min) were then bubbled into the mixture. 4.26 g (16.03 mmol, 3.5 eq) of PPh 3was added. Cooling was removed after 1.5 hours and the mixture was stirred at room temperature overnight (KI test was negative). The solvent was evaporated under reduced pressure (Rotavap in fume hood). GC analysis gave a 1 / 1 mixture of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one and (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one. NMR analysis revealed a mixture of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one, (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid, and (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one.

[0148] This mixture was treated with oxidative (CrO 3 , acetone, heat) treatment (WO 2012 / 125488, Anderson, Eric; et al) or basic (3 eq NaOAc in EtOH, reflux, 16 h, complete conversion, selectivity >95%) treatment (Xiang, H.; Zhao, Q.-L.; Xia, P.-J.; Xiao, J.-A.; Ye, Z.-P.; Xie, X.; Sheng, H.; Chen, X.-Q.; Yang, H.Org. Lett. 2018, 20, 1363-1366) allowed complete conversion to (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one.

[0149] (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one [ka]

[0150] (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was prepared by reacting the intermediate of Example 6 ((((1S,4aS,8aS)-5,5,8a-trimethyloctahydro-1H-spiro[naphthalene-2,3'-[1,2,4]trioxolane]-1-yl)methanol) with 20 mol% Fe(NO 3 ) 3 9H 2 PPh could also be obtained by oxidation with air in the presence of 20 mol% KCl and 20 mol% TEMPO (bubbling through the solution at room temperature for 2 days). 3 After addition of 1,000,000, aqueous work-up / solvent evaporation (in a fume hood) and column chromatography, (4aS,8aS,Z)-1-(hydroxymethylene)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one could be isolated in 67% yield over two steps (ozonolysis and oxidation). A small amount (3% yield) of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one was also isolated.

[0151] [Example 19: Comparative Example] Benzyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate was prepared from (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylic acid in a two-step chemical process (BzBr, K 2 CO 3 , acetone and O 3 , PPh 3 , MeOH), or from methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate according to Pollini, GP; Bianchi, A.; Casolari, A.; Risi, C.; Zanirato, V.; Bertolasi, V. Tetrahedron: Asymmetry 2004, 15, 3223.

[0152] Benzyl (1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-1-carboxylate [ka]

[0153] Benzyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate [ka]

[0154] CDCl 3 In 1 The H-NMR analysis results were in agreement with the data in the literature (Pollini, GP; Bianchi, A.; Casolari, A.; Risi, C.; Zanirato, V.; Bertolasi, V. Tetrahedron: Asymmetry 2004, 15, 3223-3231).

[0155] Hydrogenation (according to Pollini et al Tetrahedron: Asymmetry 2004, 15, 3223) of 108 mg of benzyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate (33 mg of Pd / charcoal 10%, H 2 , 2 mL EtOH, 20 psi for 2 h) to form (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one (100% selectivity, complete conversion). No trace of (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid was observed (verified by crude silylation, methylation with trimethylsilyldiazomethane, and NMR).

[0156] [Example 20: Comparative Example] 50 mg of methyl (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylate was heated at reflux (150°C) for 5 h in the presence of 10 mg of KI in 0.5 mL of DMF (according to Ohloff, G.; Naef, E; Decorzant, R.; Thommen, W.; Sundt, E. Helv. Chim. Acta 1973, 56, 1414-1448). The formation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalene-2(1H)-one was observed (complete conversion of starting material). No traces of (1R,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-1-carboxylic acid were detected (verified by crude silylation, methylation with trimethylsilyldiazomethane, and NMR).

Claims

1. formula 【Chemistry 1】 [In the formula, bold and hatched lines indicate relative or absolute configurations] 1. A method for preparing a compound of formula (I), said method comprising: a) Formula 【Chemistry 2】 [Wherein X is vinyl, CHO, COOH, C(=O)OR １ or CH ２ OR ２ represents a group, and R １ is C １－６ represents an alkyl group, and R ２ represents a hydrogen atom, a benzyl group, C(=O)R ａ group, C(=O)OR ｂ group, C(R ｃ ) ２ OR ｄ group or Si(R ｄ ) ３ represents a group, and R ａ is a hydrogen atom or C １－６ is an alkyl group, and R ｂ is C １－６ is an alkyl group, and R ｃ are each independently a hydrogen atom or C １－２ is an alkyl group, and R ｄ is C １－４ is an alkyl group, or one of R ｃ and R ｄ Together, C ４－５ forming an oxacycloalkyl group, 【Transformation 3】 [Wherein X' is CHO, COOH, C(=O)OR １ or CH ２ OR ２ represents a group, and R １ and R ２ have the same meaning as defined above], b) converting the intermediate of formula (III) into a compound of formula (I); A method comprising:

2. 2. The method of claim 1, wherein the oxidative cleavage is ozonolysis.

3. R １ is C １－３ is an alkyl group, preferably R １ is a methyl group, and R ２ is a hydrogen atom or C(=O)R ａ group, and R ａ is a hydrogen atom or C １－３ is an alkyl group, preferably R ａ The method according to claim 1 or 2, wherein is a hydrogen atom.

4. X' is CH ２ OR ２ 3. The method of claim 1 or 2, wherein when

5. R ２ The method according to claim 4, wherein when is not a hydrogen atom, deprotection is carried out before the retro-aldol reaction.

6. The method according to claim 4, wherein the retro-aldol reaction is a thermal retro-aldol reaction.

7. 5. The process of claim 4, wherein the retro-aldol reaction is carried out in the presence of a solvent having a boiling point of 65° C. or higher, preferably 110° C. or higher.

8. X' is COOH or C(=O)OR １ 3. The method of claim 1, wherein when the intermediate of formula (III) is a group, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a decarboxylation reaction.

9. 9. The method of claim 8, wherein the decarboxylation reaction is carried out in the presence of an acid or a base.

10. X is CH ２ OH, CHO or COOH group, and X' is CH ２ OH or COOH group, preferably X is CH ２ OH group, and X' is CH ２ 3. The method according to claim 1 or 2, wherein the group is an OH group.

11. 11. The method of claim 10, wherein the compound of formula (II) is obtained by contacting farnesyl pyrophosphate with at least one enzyme.

12. The compound of formula (I) is reacted with a compound of formula 【Chemistry 4】 3. The method of claim 1 or 2, further comprising the step of converting the compound of formula (I) into a compound of formula (II) wherein the bold and hatched lines indicate relative or absolute configuration.

13. formula 【Transformation 5】 A compound of the formula: wherein the bold and hatched lines indicate relative or absolute configuration.

14. formula 【Transformation 6】 [In the formula, the bold and hatched lines indicate the relative or absolute configuration, and X is CHO, COOH, C(═O)OR １ or CH ２ OR ２ represents a group, and R １ is C １－６ represents an alkyl group, and R ２ represents a hydrogen atom, a benzyl group, C(=O)R ａ group, C(=O)OR ｂ group, C(R ｃ ) ２ OR ｄ group or Si(R ｄ ) ３ represents a group, and R ａ is a hydrogen atom or C １－６ is an alkyl group, and R ｂ is C １－６ is an alkyl group, and R ｃ are each independently a hydrogen atom or C １－２ is an alkyl group, and R ｄ is C １－４ is an alkyl group, or one of R ｃ and R ｄ Together, C ４－５ forming an oxacycloalkyl group] in any one stereoisomeric form or mixtures thereof.

15. formula 【Transformation 7】 A compound of the formula: wherein the bold and hatched lines indicate relative or absolute configuration.

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